Treatment of prosthetic joint infection. Alex Soriano Department of Infectious Diseases Hospital Clínic of Barcelona

Treatment of prosthetic joint infection Alex Soriano Department of Infectious Diseases Hospital Clínic of Barcelona

Barret L, et al. The clinical presentation of prosthetic joint infection. J Antimicrob Chemother 2014; 69: suppl 1: i25-i27 debridement, antibiotic treatment and implant retention (DAIR)

planktonic bacteria bactericidal antibiotic (5-10 d) adapted bacteria anti-biofilm antibiotic (2-6 m) persistent bacteria suppresive antibiotic (???)

Lora-Tamayo J, et al. A Large Multicenter Study of MS and MR Staphylococcus aureus Prosthetic Joint Infections Managed With Implant Retention. Clin Infect Dis 2013; 56: 182 94 retrospective & multi-centric study including 345 episodes of acute PJI MSSA: i.v. cloxacillin MRSA: i.v. vancomycin 1 m

Tornero E, et al. KLIC-score for predicting early failure in acute prsothetic joint infections treated with DAIR Clin Microbiol Infect 2015; 21: 786

Tornero E, et al. KLIC-score for predicting early failure in acute prsothetic joint infections treated with DAIR Clin Microbiol Infect 2015; 21: 786 5%

% remission / failure C-reactive protein before debridement (mg/dl) Tornero E, et al. KLIC-score for predicting early failure in acute prsothetic joint infections treated with DAIR Clin Microbiol Infect 2015; 21: 786 N=114 (56%) N=54 (26%) N=36 (18%)

Tornero E, et al. KLIC-score for predicting early failure in acute prsothetic joint infections treated with DAIR Clin Microbiol Infect 2015; 21: 786 high planktonic bacterial load

Dastgheyb S, et al. Staphylococcal Persistence Due to Biofilm Formation in Synovial Fluid Containing Prophylactic Cefazolin. Antimicrob Agents Chemother 2015; 59:2122 2128 Staphylococcus aureus x10 PIA/PNAG staining 3D- confocal laser microscopy

Dastgheyb S, et al. Effect of Biofilms on Recalcitrance of Staphylococcal Joint Infection to Antibiotic Treatment. J Infect Dis 2015; 211: 641-50

Thompson JM, et al. Oral-Only Linezolid-Rifampin Is Highly Effective Compared with Other Antibiotics for Periprosthetic Joint Infection J Bone Joint Surg (Am) 2017; 99:656-65 1. inoculum 10 3 CFU of bioluminiscent MRSA 2. After a 2-week incubation period to allow biofilm formation on the Kirschner 3. Antibiotic treatment (or sham treatment with saline solution) was initiated for 6 weeks with doses that approximate human-exposure doses according to the AUC and differences in serum drug protein binding between mice and humans

Achermann Y, et al. Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case control study. Infection 2013; 41: 431-7 variable male 3 prior revision surgeries rifampin treatment - high bacterial load - no debridement - monotherapy - combine with non active atb - no intravenous atb P-value 0.02 0.006 <0.05 There is an unwritten rule that advise against the use of rifampin the first 1-2 weeks after debridement Case-control study. Cases (n=48) and controls (n=48)

planktonic bacteria bactericidal antibiotic (5-10 d) debridement + PE exchange C-RP < 10 mg/dl: cloxacillin / linezolid / daptomycin /ceftaroline C-RP 10 mg/dl: association of 2 atb (fosfomycin) Local antibiotics?: gentamicin beads have been associated with a worse outcome (Lowik C, et al. J Arthroplasty 2018) adapted bacteria anti-biofilm antibiotic (2-6 m)

Otero LH, et al. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. PNAS 2013; 110: 16808-16813 PBP2A (MRSA) ß-lactams bind in a distal site (alosteric site) Mahasenan KV, et al. JACS 2017; 139; 2102-2110

Saravolatz LD, et al. Ceftaroline: A Novel Cephalosporin with Activity against Methicillin-resistant Staphylococcus aureus Clinical Infectious Diseases 2011;52(9):1156 1163 MIC 90 (µg/ml) MIC 90 (µg/ml). For GNB, has an activity similar to ceftriaxone

v Remission rates with different oral antibiotic regimens in staphylococcal prosthetic joint infections Senneville CID 2011 N=98 (%) Tornero IJAO 2012 N=106 (%) Surgical treatment: DAIR or Ex DAIR Microorganims: S. aureus S. aureus & CoNS Oral options*: FQ+Rif LNZ (+/-Rif) others 37/39 (94.8) 9/11 (81.8) 31/48 (64.5) 44/50 (88) 26/32 (81) 22/28 (78.5) * after 1 week of intravenous antibiotic with vancomycin and a ß-lactam

Viale P, et al. Treatment of pyogenic (non-tuberculous) spondylodiscitis with tailored high-dose levofloxacin plus rifampicin Int J Antimicrob Agents 2009; 33: 379-82 Levo (750 mg/24h) + rifa 600 mg/24h

Zeller V, et al. Continuous Clindamycin Infusion, an Innovative Approach to Treating Bone and Joint Infections Antimicrob Agents Chemother 2010; 54: 88-92 Continuous infusion 30-40 mg/kg/24h (2-3 g/24h for 70 kg) 30-40%

Ribera E, et al. Rifampin Reduces Concentrations of Trimethoprim and Sulfamethoxazole in Serum in HIV-Infected Patients. Antimicrob Agents Chemother 2001; 45: 3238-41 Serum concentration of trimethroprim decreased 47% and sulfametoxazol 23%

Gandelman K, et al. Unexpected Effect of Rifampin on the Pharmacokinetics of Linezolid: In Silico and In Vitro Approaches to Explain Its Mechanism. J Clin Pharm 2011; 52: 229-236 Linezolid 600 mg Linezolid 600 mg + Rifampicina 600 mg

Tornero E, et al. Importance of selection and duration of antibiotic regimen in prosthetic joint infections treated with debridement and implant retention J Antimicrob Chemother 2016; 71:1395-1401 grampositives Lev+Rif Lin+Rif Lin

Pushkin R, et al. A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination with Oral Rifampin Compared with Standard of Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction. Clin Infect Dis 2016; 63: 1599-1604. FA (1200-1500 mg/24) + RIF (450 mg/12h) n= 7 Stopped RIF 2 failures 1 MRSA RIF-R

Cheng M, et al. Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin. Org. Biomol. Chem 2014; 12: 2568 dalbavancin (derivative of teicoplanin)

Mature PG GP (dalbavancin) Nascent PG Transpeptidation Transglycosilation C55 PBP Antibiotic dalbavancin vancomycin daptomycin MIC 90 (mg/l) for Staphylococcus spp 0.06 2 0.5 MIC 90 (mg/l) for Enterococcus spp 0.06-0.12 2 2

mg/l Dorr MB et al. Human pharmacokinetics and rationale for onceweekly dosing of dalbavancin, a semi-synthetic glycopeptide J Antimicrob Chemother 2005;55 (Suppl2):25-30 300 250 Renal adjustment: - GF<30 ml/min: 750mg+375mg (ó 1g) 200 150 100 50 0 1000 mg (30 ) 1500 mg (30 ) free >20 mg/l, PBS frente a SARM* 0 8 14 days 500 mg (30 ) * Leighton, et al. AACh 2004

1000 mg DLB Dunne MW, et al. Extended duration dosing and distribution of dalbavancin into bone and articular tissue. Antimicrob Agents Chemother 2015; 59:1849 1855

Rappo U, et al. Long-term outcomes of dalbavancin for the treatment of osteomyelitis in adult patients. 28th ECCMID 2018, Madrid, Spain. Abst 697 * implant-associated infections were excluded

Rappo U, et al. Long-term outcomes of dalbavancin for the treatment of osteomyelitis in adult patients. 28th ECCMID 2018, Madrid, Spain. Abst 697 1500 mg day 1 1500 mg day 7

Rappo U, et al. Long-term outcomes of dalbavancin for the treatment of osteomyelitis in adult patients. 28th ECCMID 2018, Madrid, Spain. Abst 697

Barret L, et al. The clinical presentation of prosthetic joint infection. J Antimicrob Chemother 2014; 69: suppl 1: i25-i27 debridement, antibiotic treatment and implant retention (DAIR)

% survival Wouthuyzen-Bakker, M et al. Late acute prosthetic joint infections treated with DAIR; outcome and risk factors for failure (ESGIAI). 340 patients (27 centers) Definition: < 3 weeks of symptoms > 3 months after the index surgery a prior history of normal function 60% 45% 27% Failure: related death Prosthesis removal Suppressive therapy

Wouthuyzen-Bakker, M et al. Late acute prosthetic joint infections treated with DAIR; outcome and risk factors for failure (ESGIAI). Variables OR P-value Fracture as indication for prosthesis 5.4 0.01 Rheumatoid arthritis 5.1 0.04 Chronic obstructive pulmonary disease 2.9 0.05 Age above 80 years 2.6 0.02 Male Gender 2.0 0.04 C-reactive protein > 150 mg/l 2.0 0.04 Exchange of mobile components 0.35 0.002 340 patients (27 centers)

% failure Wouthuyzen-Bakker, M et al. Late acute prosthetic joint infections treated with DAIR; outcome and risk factors for failure (ESGIAI). 19 56 18 68 124 340 patients (27 centers)

% survival Wouthuyzen-Bakker, M et al. Late acute prosthetic joint infections; should the imlant be removed? (ESGIAI). Implant removal (n=105) 75% Implant retention (n=340) A propensity-matching score analysis (81:81) confirm these results (48% vs. 74%, P=0.001) 55% 445 patients (27 centers)

Wouthuyzen-Bakker, M et al. Late acute prosthetic joint infections; should the imlant be removed? (ESGIAI). Late acute PJI (n=395) % of FAILURE CRIME80 3 n=107 (retention 83% vs. removal 31%) CRIME80 < 3 n=288 S. aureus (n=125) (retention 45% vs. removal 25%) other (n=163) (retention 29% vs. removal 23%) IMPLANT REMOVAL No RA PE exchange CRP<15 mg/dl Suscept to Rif IMPLANT RETENTION

Kunutsor SK, et al. One- and two-stage surgical revision of periprosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies. Eur J Epidemiol 2018; 97: 1368 Reinfection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6 20.7) and 32.3 (95% CI 27.3 38.3) for 1-stage and 2- stage strategies respectively.

EUROPEAN BONE AND JOINT INFECTION SOCIETY 6-8 SEPTEMBER 2018 - HELSINKI, FINLAND The conference will be held in the white marble and granite faced Finlandia Hall. The congress venue is situated beautifully in a park near the sea in the centre of Helsinki, in the vicinity of several hotels- DEADLINES ABSTRACT SUBMISSION: 20 APRIL 2018 EARLY REGISTRATION: 1 JULY 2018 We look forward to welcoming you to Helsinki!